Identification of Small Molecule Ligands with NGF Potentiating Activity

具有 NGF 增强活性的小分子配体的鉴定

基本信息

批准号：
7683033
负责人：
Gordon C Ibeanu
金额：
$ 9.84万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683033
关键词：
Affinity Alzheimer&apos s Disease Area Biological Assay Biological Factors Blood - brain barrier anatomy Cell Line Cell Lineage Cell model Cells Chemicals Chemistry Chemosensitization Collection Complex Cues Data Data Quality Defect Dementia Development Enhancers Enzyme-Linked Immunosorbent Assay Fostering Foundations Funding Future Gene Expression Regulation Goals Human Huntington Disease In Vitro Laboratory Research Lateral Lead Ligands Measures Messenger RNA Methods Molecular NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Nerve Growth Factors Neurites Neurodegenerative Disorders Neuronal Differentiation Neurons Neurosciences Outcome Pathway interactions Patients Peptides Pharmacologic Substance Plants Process Property Proteins Publications Regulation Research Research Personnel Role Signal Pathway Small Molecule Chemical Library Specificity Structure Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Translating United States National Institutes of Health Work age related cellular targeting computational chemistry high throughput screening in vivo nervous system disorder neurite growth neurodevelopment neuron loss neurotrophic factor neurotropic novel prevent programs research study scaffold small molecule small molecule libraries tool transmission process

项目摘要

The specific aims of the research described in this application is to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action n promoting neuronal differentiation and survival with regards to new pathways and cellular targets. The objectives in the long-term are to develop invaluable tools to better understand the general mechanisms of activity potentiation and the roles of NGF in fostering the development of neural processes. Identified leads with acceptable therapeutic profiles will progress through SAR with the ultimate goal to develop therapeutic agents that prevent or delay the onset of neurodegeneration caused by defects in molecular and chemical cues that initiate and sustain neurite extension. This research will utilize the approaches of chemoinformatics and HTS to identify novel structures and molecules with core chemical scaffolds that are similar to known potentiators of NGF-dependent neurite extension of natural products origin from a chemical library of small molecules. Active compounds will be characterized for potency, efficacy, selectivity, and specificity in neuronal cell lineages to identify lead compounds. Studies on the mechanism of actions of leads compounds will be initiated to establish novel pathways and cellular targets that interact with identified leads. Successful development of NGF potentiators with therapeutic values will have a tremendous impact in modifying the outcome of age-related neurodegenerative diseases and other dementias.

本应用中描述的研究的具体目的是发展新颖的有效和选择性小 NGF依赖性活性在神经元中的分子增强剂，并表征其作用机理 n促进了关于新途径和细胞靶标的神经元分化和存活。这长期的目标是开发宝贵的工具，以更好地了解活性增强和NGF在促进神经过程发展中的作用。确定的线索具有可接受的治疗特征将通过SAR进行发展，并具有开发治疗的最终目标预防或延迟由分子和化学缺陷引起的神经变性发作的药物引发和维持神经突扩展的提示。这项研究将利用化学信息和HTS鉴定具有核心化学支架的新结构和分子类似于NGF依赖性神经突扩展的天然产物延伸的已知电位。小分子库。活性化合物将以效力，功效，选择性和神经元细胞谱系中的特异性以鉴定铅化合物。研究动作机制将启动铅化合物，以建立与鉴定的新型途径和细胞靶标的相互作用铅。成功开发具有治疗价值的NGF增强器将产生巨大影响在修改与年龄相关的神经退行性疾病和其他痴呆症的结果时。